The present invention relates to bidentate ligands that are capable of forming complexes with various metallic centers such as platinum, palladium and ruthenium. It relates particularly to ligands that can form metal-containing complexes that are transportable in vivo by liposomes or injected fluorocarbon emulsions.
It is indeed known that numerous transition metal complexes, particularly palladium and platinum complexes, have a chemotherapeutic activity, as described in U.S. Pat. No. 4,584,316. However, the complexes used at present have a therapeutic index (efficacy/toxicity ratio) which is still too low. Their excessive toxicity limits their use, notably on account of the risk of renal lesions.
One way of reducing this major disadvantage is to "isolate" these complexes by incorporation into or association with a vector, permitting a slower diffusion of the active principal. The encapsulation into liposomes of cis-platinum (Freise, J., W. H. Mueller, P. Magerstedt, H. J. Schmoll (1982) Arch. Int. Pharmacodyn., 258,180) and analogs thereof (Khokhar, A. R., S. Al-Baker, R. Perez-Soler (1988) Anticancer Drug Design 3, 177), reduces the efficacy of these agents, but improves the therapeutic index, prolongs their action, favorably modifies their biodistribution, and even promotes the induction of an antitumor activity against resistant tumors. However, the insertion of the known complexes into the lipidic membrane of the vector is not totally satisfactory, because the present ligands of these complexes are not sufficiently hydrophobic.